Growth hormone (GH) is a polypeptide hormone normally synthesized and secreted by the somatotrophic cells of the anterior lobe of the pituitary gland. The secretion of GH is tightly regulated by an integrated system of neural, metabolic and hormonal factors. Although GH is present throughout life, its secretion is both age- and sex-dependent.
GH binds to specific receptors on hepatocytes, fibroblasts and lymphoid cells. The known physiological roles of GH are probably due to both direct actions and indirect actions that are mediated by insulin-like growth factors, IGFs. IGFs are themselves peptide hormones, whose secretion is stimulated predominantly by the action of GH, and include IGF-I and IGF II. The major site of IGF production is the liver, but there may also be synthesis at peripheral sites.
GH has profound effects not only on growth, but also on body composition and metabolism. Via the IGFs, GH increases protein synthesis by enhancing amino acid uptake and directly accelerating the transcription and translation of mRNA. In addition, GH tends to decrease protein catabolism by mobilizing fat as a more efficient fuel source. This protein sparing effect may be the most important mechanism by which GH promotes growth and development. GH also affects carbohydrate metabolism. There are suggestions that short-term constant infusion of GH has insulin-like effects, whereas GH in excess decreases carbohydrate utilization and impairs glucose uptake into cells, showing an anti-insulin effect. This GH-induced insulin resistance appears to be due to a post-receptor impairment in insulin action and results in glucose intolerance that in turn stimulates insulin secretion. In normal development, GH and IGFs are responsible for many of the manifestations of normal growth. Growth hormone deficiency (GHD) is manifested by a marked short stature.
The treatment of GHD began in 1958. Due to the species specificity of GH, treatment can only be performed by using human growth hormone (hGH), which at that time could only be obtained by purifying pituitary glands collected at necropsy. Because of the limited number of pituitary glands available, a world-wide shortage of hGH occurred and its use was restricted to severely growth retarded children with GHD. Recombinant DNA technology made it possible to produce a biosynthetic GH identical to hGH. Clinical studies of recombinant hGH (r-hGH) began in 1981 and the response of children with GHD to r-hGH therapy has been well documented. Moreover, the production of r-hGH has allowed further investigation of the anabolic potential of this compound. Recent studies with r-hGH have shown that supraphysiological doses promote positive nitrogen balance, improve body protein homeostasis under catabolic conditions, and may accelerate recovery during critical illness in many groups of subjects.
Subcutaneous (s.c.) hGH administration is occasionally hampered by administration difficulties and local irritation. The continuous use of s.c. hGH in children is particularly problematic. An oral form of hGH would improve patient acceptance and facilitate improved patient compliance by providing a more acceptable delivery route for peptide therapy.
There have been many attempts to promote absorption of poly (amino acids) such as peptide and proteins, e.g. hormones. It is generally believed that peptides and proteins need to be protected from the gastric and intestinal environment, where many peptidases exist and significant degradation may occur. Enteric coating and the addition of peptidase inhibitors to pharmaceutical compositions have proven to be effective in improving poly(amino acid), e.g. protein and peptide, absorption via oral administration. However, those approaches alone do not offer sufficient protection to achieve a satisfactory plasma level of a peptide or a protein, such as human growth hormone.
Carrier compounds and compositions which are useful in the delivery of active agents have been suggested, among other things for delivering peptide or protein active agents. WO 98/34632 A1 discloses amino acid derivatives as carrier compounds which are suited to form non-covalent mixtures with biologically-active agents. Among the compounds is 8-(N-2 hydroxy-5-chlorobenzyl)aminocaprylic acid (compound #109). This compound may also be referred to as N-(5-chlorosalicyloyl)-8-aminocaprylic acid and will herein be abbreviated as 5CNAC.
WO 98/34632 A1 furthermore discloses solutions containing a carrier compound and recombinant human growth hormone (Example 4). Several carriers are investigated, among them 5-CNAC (i.e. 8-(N-2-hydroxy-5-chlorobenzyl)aminocaprylic acid, compound #109). The compound is contained in an intracolonic dosing composition in a weight ratio of carrier to growth hormone of 25:1. The intracolonic dosing composition is administered to anaesthetised rats by intracolonic instillation (Example 5), and the serum level of human growth hormone after administration is determined.
For some other carriers, WO 98/34632 A1 describes oral solutions having a weight ratio of carrier to growth hormone of 200:1 that are also tested in rats.
WO 98/34632 A1 contains no data relating to administration of growth hormone to humans and also contains no evidence for biological activity of the administered growth hormone. There is no disclosure of a solid oral dosage form, such as a capsule or a tablet.
WO 00/59863 A1 discloses disodium salts, monohydrates and ethanol solvates of certain delivery agents, among them N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC).
WO 00/59863 A1 also suggests compositions containing various active agents. Human growth hormone is mentioned in a long list of active agents, but there is no growth hormone formulation examplified, and there are no data regarding the administration of any growth hormone formulation. For a composition containing a preferred active agent according WO 00/59863 A1, namely calcitonin. weight ratios of active agent to 5-CNAC of about 1:300 to 1:700 are suggested (WO 00/59863 A1, page 8).
WO 2005/004900 A1 describes orally dosed pharmaceutical compositions comprising a delivery agent in micronized form. 5-CNAC is among the delivery agents mentioned. WO 2005/004900 A1 furthermore mentions growth hormone as an active agent, but there are no details disclosed for the specific combination, and there are also no data relating to the administration of growth hormone to patients. The only exemplified formulation comprises salmon calcitonin and 5-CNAC in a weight ratio of 1:228.
While the prior art suggests in general terms to combine active agents such as hGH with a carrier compound, such as 5-CNAC, there are no data that would demonstrate that an hGH oral dosage form shows biological effects, such as stimulation of IGF production. Furthermore, the prior art seems to indicate that a significant excess of carrier compound relative to biologically active ingredient, such as human growth hormone, is needed for absorption. Nevertheless, it remains unclear whether the absorbed material shows the biological activities of human growth hormone, such as stimulation of an IGF-I response.
Despite the above suggestions regarding delivery of peptide and protein active agents, hGH is currently still administered by injection. There exists a long-felt need for an oral dosage form, in particular a solid oral dosage form, such as a capsule or tablet.
Thus, it is an object of the present invention to provide pharmaceutical compositions useful for the oral administration of hGH.
Furthermore, it may be advantageous to use relatively small amounts of carrier or delivery agent in relation to the active agent, in particular for dosage forms containing human growth hormone in a therapeutically effective amount of, for instance in the order of 100 mg, as such dosage forms would have advantages in administration, e.g. would be easier for a patient to swallow.
Thus, it is a further object of the invention to provide useful solid oral dosage forms which contain therapeutically effective amounts of human growth hormone.
Although 5-CNAC is generally well-tolerated, there is a desire to avoid exposure to excessive amounts of the agent, in particular during long-term administration.
Thus, it is a still further object of the invention to provide dosage forms of human growth hormone which are suitable for oral delivery of the active agent, but which avoid the exposure of the patient to large amounts of delivery agents, such as 5-CNAC.